There are two types of inflammation: acute inflammation and low grade chronic inflammation.

Acute inflammation is the body’s response to tissue injury like a scratch on the leg or the presence of an infection such as a virus or harmful bacteria. Acute inflammation causes the well known signs and symptoms: redness, warmth, swelling, and pain around tissues that occurs in response to an injury. These symptoms develop because the immune system releases white blood cells to surround and protect the damaged area.

The body’s response to injury or infection is to trigger several processes in the body. For example, a certain type of white blood cell called mast cells release histamine, heparin, and prostaglandins. These chemicals increase blood flow to the affected area and cause blood vessels to dilate. By becoming dilated, blood vessels can release more oxygen, nutrients and immune cells for repair and remove more toxins and waste from the affected area.

Chemicals released by mast cells and the resulting abnormal conditions within the tissues stimulate nerve endings to release a pain signal to the brain.

If damaged cells are stabilised the body will stop activating mast cells in that area which means they will stop releasing histamine, heparin, and prostaglandins. Regeneration will then begin to occur with fibroblasts moving into the area to rebuild tissue back to a normal healthy state ¹.

This process works well if we have sustained an injury like scratching our leg or catching an infection like a cold or the flu that we eventually get over. However, if our gut microbiome becomes inhabited by harmful bacteria that produce toxins and damage tissue, our body may continue to release inflammation for as long as that harmful microbe resides in the gut. This can lead to a state of what’s called chronic low grade inflammation where our body is having an inflammatory response for months or years.

Continuous inflammation may cause a cascade of issues throughout the body that could result in migraines, allergies, altered blood pressure, and hormonal issues ^{2, 3, 4} .

¹ Martini, F., Nath, J., Bartholomew, E., 2018. “Fundamentals of Anatomy & Physiology”. 11th Edition. Pearson Education Limited, Essex, England.

² Sjaarda, L. A., Radin, R. G., Swanson, C., Kuhr, D. L., Mumford, S. L., Galai, N., Silver, R. M., Wactawski-Wende, J., Perkins, N. J., & Schisterman, E. F. (2018). Prevalence and Contributors to Low-grade Inflammation in Three U.S. Populations of Reproductive Age Women. Paediatric and perinatal epidemiology, 32(1), 55–67. https://doi.org/10.1111/ppe.12409

³ Larsen SB, Grove EL, Würtz M, Neergaard-Petersen S, Hvas AM, Kristensen SD. The influence of low-grade inflammation on platelets in patients with stable coronary artery disease. Thromb Haemost. 2015;114(3):519-529. doi:10.1160/TH14-12-1007

⁴ Hatziagelaki E, Pergialiotis V, Kannenberg JM, et al. Association between Biomarkers of Low-grade Inflammation and Sex Hormones in Women with Polycystic Ovary Syndrome. Exp Clin Endocrinol Diabetes. 2020;128(11):723-730. doi:10.1055/a-0992-9114

Chronic Inflammation may trigger migraines in a number of ways, two of which are via endothelial cell and red blood cell dysfunction. Endothelial cells line the inside of blood vessels and red blood cells carry oxygen and nutrients around the body. If either of the cells aren’t functioning properly it can result in a lack of blood flow around the brain leading to migraine.

Endothelial cell dysfunction

Inflammation is associated with oxidative stress which impacts, amongst other things, endothelial cells in the brain. These cells form a single layer that lines all blood vessels and regulates exchanges between the bloodstream and nearby tissues. When endothelial cells dysfunction in the brain they can cause a brief narrowing of blood vessels that restricts blood flow to some areas of the brain causing migraine.

Red blood cell dysfunction

Inflammation and oxidative stress leads to red blood cell dysfunction. By having red blood cell dysfunction a person is more likely to have micro-clots in the brain that further restricts the flow of oxygen and nutrients ¹ which can lead to migraines.

Restricted blood flow in the brain

The brain needs more oxygen than all other major organs and therefore is more sensitive if blood flow is restricted. Although it represents only 2% of body weight, the brain consumes about 20% of the oxygen that a person takes in. The restricted blood flow means oxygen, which is carried in the blood, doesn’t get delivered to where it needs to go. This then triggers the release of inflammation in those areas of the brain that don’t have enough oxygen which stimulates neurons to fire a pain response and gives you the sensation of a migraine.

¹ de Villiers S, Bester J, Kell DB, Pretorius E. A Possible Role of Amyloidogenic Blood Clotting in the Evolving Haemodynamics of Female Migraine-With-Aura: Results From a Pilot Study. Front Neurol. 2019;10:1262. Published 2019 Nov 26. doi:10.3389/fneur.2019.01262

There are different types of inflammation. Some inflammation types known to be associated with migraines include interleukin IL1, IL6, IL10 and TNFa ^{1, 2, 3}. When doctors order blood tests they typically include a test for either or both of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Neither of these tests cover interleukins or TNFa ¹.

This means that a person that returns a result of “low inflammation” from routine blood tests may actually have high inflammatory markers associated with migraines because they simply weren’t tested for.

¹ Martami, F., Razeghi Jahromi, S., Togha, M. et al. The serum level of inflammatory markers in chronic and episodic migraine: a case-control study. Neurol Sci 39, 1741–1749 (2018). https://doi.org/10.1007/s10072-018-3493-0

² Wang, F., He, Q., Ren, Z. et al. Association of serum levels of intercellular adhesion molecule-1 and interleukin-6 with migraine. Neurol Sci 36, 535–540 (2015). https://doi.org/10.1007/s10072-014-2010-3

³ Obesity, migraine, and chronic migraine Possible mechanisms of interaction Marcelo E. Bigal, Richard B. Lipton, Philip R. Holland, Peter J. Goadsby Neurology May 2007, 68 (21) 1851-1861; DOI: 10.1212/01.wnl.0000262045.11646.b1

Yes, many people with an overgrowth of dysbiotic bacteria, pathogens, and fungal bacteria that cause inflammation may have no significant or noticeable gut symptoms.

Many factors are involved in the development of migraines and gut dysbiosis, if present, may play an essential role. One way to learn about your microbiome is to test and have the results analysed by a health professional trained in the gut microbiome and migraines.

The microbiome is diverse and test results need to be read by someone who understands how specific microbes affect the body and that has clinical experience in understanding how to resolve gut disorders without harming beneficial microbes.

Maybe. If you’ve been having acid reflux and indigestion for some time there are a few reasons why this happens. Food sensitivities, certain medications (i.e. antibiotics, PPIs, NSAIDs), gut infections, gut diseases like IBS and SIBO, and stress can all increase the risk of acid reflux and migraines as well. Furthemore, imbalances in the autonomic nervous system ¹ and excess glutamate in the brain can contribute to the development of both migraines and acid reflux ².

¹ Milovanovic B, Filipovic B, Mutavdzin S, Zdravkovic M, Gligorijevic T, Paunovic J, Arsic M. Cardiac autonomic dysfunction in patients with gastroesophageal reflux disease. World J Gastroenterol. 2015 Jun 14;21(22):6982-9. doi: 10.3748/wjg.v21.i22.6982. PMID: 26078576; PMCID: PMC4462740.

² Arzani, M., Jahromi, S.R., Ghorbani, Z. et al. Gut-brain Axis and migraine headache: a comprehensive review. J Headache Pain 21, 15 (2020). https://doi.org/10.1186/s10194-020-1078-9

Constipation can make migraines worse. If you only have constipation once in a while, that’s no problem, however, if it’s something you regularly experience and have been for some time, it can cause problems.

How constipation decreases your detox capability

The liver is the main body’s detoxifying organ, it pulls toxins out of the body and sends them to the colon to exit in the stool. If the stool sits in the colon for too long these toxins may be reabsorbed by the body and sent back to the liver overloading the liver and reducing its detoxification capability. This can result in a significant rise in inflammation further contributing to migraines.

How constipation can disrupt your hormones

Another way constipation can make migraines worse is by contributing to estrogen dominance. This is because constipation interferes with the body’s detoxification process which, when working properly, prevents the reabsorption of the estrogen-like compounds. When the bowels don’t empty properly excess extrogen can’t be eliminated in the feces, leading to estrogen dominance (more estrogen relative to progesterone, i.e. estrogen has become dominant over progesterone). This causes a cascade of problems throughout the body resulting in imbalances of other hormones and inflammation. Excess estrogen is associated with several signs and symptoms including headaches, weight gain, bloating, abnormal uterine bleeding, stomach pain and cramps ¹.

Research has also shown that estrogen delays gastric emptying, prolongs transit timing and causes constipation whereas progesterone increases gastric emptying. So when estrogen is dominant over progesterone women may experience more constipation ².

¹ Delgado, B., & Lopez-Ojeda, W. (2021). Estrogen. Statpearls Publishing. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK538260

² Chen TS, Doong ML, Chang FY, Lee SD, Wang PS. Effects of sex steroid hormones on gastric emptying and gastrointestinal transit in rats. Am J Physiol. 1995;268(1 Pt 1):G171-G176. doi:10.1152/ajpgi.1995.268.1.G171

Allergies and allergic asthma have been shown to flare up during thunderstorms ¹. A key reason why this happens is because a thunderstorm increases the amount of pollen or fungal spores in the air. Based on research studies, allergies and allergic asthma are associated with high levels of histamine in the body ². Histamine is released from mast cells in the body as an immune response. People with gut dysbiosis can have an upregulated immune system in response to excess toxins and or histamine entering the body from the gut from histamine producing gut bacteria. That state of a heightened immune system makes these people more vulnerable to allergens such as pollen and fungal spores during a thunderstorm. Their body reacts to the allergens by releasing even more histamine which causes an influx of inflammation and triggers a migraine.

¹ Anderson W, Prescott GJ, Packham S, Mullins J, Brookes M, Seaton A. Asthma admissions and thunderstorms: a study of pollen, fungal spores, rainfall, and ozone. QJM. 2001 Aug;94(8):429-33. doi: 10.1093/qjmed/94.8.429. PMID: 11493720.

² Yamauchi K, Ogasawara M. The Role of Histamine in the Pathophysiology of Asthma and the Clinical Efficacy of Antihistamines in Asthma Therapy. Int J Mol Sci. 2019;20(7):1733. Published 2019 Apr 8. doi:10.3390/ijms20071733

Sinus issues, allergies, and histamine

A person that has an abnormal immune response may have high levels of histamine and release histamine more often than someone with a normal functioning immune system. Histamine response in the nose has been shown to play a causal role in inflammatory conditions of the nose and sinuses ¹. For allergies, histamine release is the reaction that causes sneezing, itching and a runny nose.

When histamine is released by cells it boosts blood flow to that area of the body which causes inflammation. That inflammatory cell enters the blood steam and can trigger migraines.

By optimising immune system function and lowering histamine levels, sinus issues, allergies and migraines may improve.

¹ Klimek L, Casper I, Wollenberg B, Stauber R, Koennecke M. Histaminrezeptoren bei chronisch-entzündlichen Erkrankungen der Nase und Nasennebenhöhlen [Histamine receptors in chronic inflammatory diseases of the nose and paranasal sinuses]. HNO. 2019 May;67(5):389-400. German. doi: 10.1007/s00106-019-0649-z. PMID: 30944947.

Histamine levels are tested through a blood test. At Soothed we understand the causes of high levels of histamine and how this impacts migraines. Our approach to migraine resolution includes the identification and resolution of high levels of histamine.

Hormonal imbalances are identified through testing, which typically involves a urine test that can identify not only hormone levels but which pathways have been taken in the production or metabolism of hormones. This is important as someone may have normal total levels of a given hormone, however, if they are produced or cleared through impaired pathways this may trigger migraines.

At Soothed we use advanced hormone tests that show both the levels of hormones and the pathways taken in their production and elimination.

Gut Dysbiosis as a Hormonal Disruptor

When the microbiome develops an overgrowth of certain bacteria normally found in the gut (dysbiosis), or harbours specific types of pathogenic microbes, the body’s hormones can become disrupted.

Microbes also directly influence hormones which control many different body systems such as reproductive organs, metabolism, and the brain.

Estrogen, for example, is a hormone recycled by certain bacteria in the gut to be reused in the body. If these bacteria become overgrown then too much estrogen is recycled which may cause heavy periods, an overactive immune system, weight gain and inflammation which can lead to migraine.

Endotoxins, produced by gram negative bacteria in the gut as described above, are another example of how the microbiome can disrupt hormones. When in excess, endotoxins cause the body to be in a state of chronic inflammation that can result in a cascade of effects including decreasing testosterone (a vital hormone in women too) and progesterone. Estrogen dominance describes a state where estrogen levels are too high relative to progesterone levels. This state produces excess inflammation increasing the intensity and frequency of migraines and causes extreme fatigue and depression in some people. Elevated estrogen can also cause heavy periods, anaemia and an overactive immune system worsening the overall condition.

Dysbiosis can cause inflammation in the gut that can have far reaching consequences. For example, gut inflammation is known to lower the hormone melatonin that helps you sleep by calming the body down before bed. Melatonin has also been shown to have strong anti-inflammatory and antioxidant effects as described above. Without normal levels of melatonin, greater amounts of inflammation and toxins circulate in the body increasing the intensity and frequency of migraines.

The link between migraines and menstruation is well established. More than a half of women with migraines have acute attacks, often without aura, prior to menstruation or during ovulation ¹.

About 2 – 3 days before menstruation many women experience more severe symptoms. This is the late stage of the luteal phase of the cycle which sees progesterone (a calming hormone) rapidly decline from its heights during the mid luteal phase. See figure 1 below.

Figure 1. Menstrual Cycle Patterns in Healthy Women ². Premenstrual phase begins from around day 23 to 24 through to the onset of menstruation as highlighted in blue.

The dramatic reduction in the calming hormone progesterone is responsible for fluid retention, which may exacerbate bloating and other gut symptoms. Many women will experience less frequent bowel movements during this phase that may impair detoxification.

Increased toxic load

The role of the liver is to pull toxins out of the body and excretes them into bile for elimination out of the body through the stool. The liver receives toxins from the body that are attached to fats (fat soluble) and in order for them to be eliminated in stool and urine they must be attached to water (become water soluble). The liver does this by using, amongst other things (see below), glucuronic acid that it attaches to toxins and converts them from fat soluble to water soluble.

For those of us whose microbiome is not as good as it could be, we can have an excess of beta glucuronidase producing bacteria. These bacteria live in the gut and remove glucuronic acid from toxins making them fat soluble again and sending them back to the liver. During PMS our colon slows down and we may become a little constipated. This gives beta glucuronidase producing bacteria more time to do their work increasing the amount of toxin going back to the liver which can make us feel nauseous and produces an excess of inflammation causing migraines and depression ³ in some people.

In addition to the glucuronidation pathway (described above), the liver has another five main pathways to detoxify the body from harmful substances.

The sulfation pathway involves the addition of a sulphate group (SO2-4) to chemicals including endotoxins, Tylenol, and some environmental toxins. This pathway also promotes the elimination of residual hormones, and neurotransmitters.

The glutathione transferase pathway involves the addition of glutathione to chemicals like heavy metals, solvents and pesticide using the enzyme called glutathione transferase.

The acetylation pathway helps detoxify the body, as well. It involves the attachment of a compound called Acetyl CoA to various chemicals from the environment.

The amino acid conjugation pathway helps detoxify the body by promoting the elimination of solvents, some food preservatives and some environmental chemicals.

The methylation pathway. Methylation involves the addition of a methyl group (-CH3) to certain hormones, neurotransmitters, drugs, or toxins to render them water soluble. Genetic variations related to the methylation cycle can therefore predispose a person to decreased ability to detox and a wide range of conditions – including mental emotional symptoms, migraines and hormonal imbalances.

¹ Dzator JSA, Howe PRC, Griffiths LR, Coupland KG, Wong RHX. Cerebrovascular Function in Hormonal Migraine: An Exploratory Study. Front Neurol. 2021 Jul 7;12:694980. doi: 10.3389/fneur.2021.694980. PMID: 34305799; PMCID: PMC8292610.

² Draper, C.F., Duisters, K., Weger, B. et al. Menstrual cycle rhythmicity: metabolic patterns in healthy women. Nature Sci Rep 8, 14568 (2018). https://doi.org/10.1038/s41598-018-32647-0

³ Beurel E, Toups M, Nemeroff CB. The Bidirectional Relationship of Depression and Inflammation: Double Trouble. Neuron. 2020 Jul 22;107(2):234-256. doi: 10.1016/ j.neuron.2020.06.002. Epub 2020 Jun 17. PMID: 32553197; PMCID: PMC7381373.

It can be. Anemia results in the release of inflammation with increased interleukin IL-1, IL-4 and IL-6 known to trigger migraines.

Iron plays a major role in the synthesis of serotonin, dopamine and norepinephrine and iron deficiency anemia is associated with migraines in women ¹.

The question becomes, what’s causing the anemia?

Is it iron deficiency anemia or anemia of inflammation?

If you’ve read this far you may have been diagnosed with anemia by your doctor and told you need to increase your iron intake from foods high in iron or take an iron supplement. You may have found that this approach hasn’t resolved your anemia. This is quite possible due to the underlying chronic inflammation associated with migraines.

Migraines are often a chronic inflammatory condition and we know that chronic inflammation reduces the body’s ability to absorb and utilise iron for red blood cell production. Inflammation increases the production and release of hepcidin (an iron regulating peptide) from the liver. Hepcidin inhibits iron absorption in the duodenum (the first part of the small intestine) and also stops the release of iron from white blood cells ².

Also, if you have an overgrowth of gram negative bacteria in your gut the lipopolysaccharides produced by these bacteria push the body towards storing iron over utilising iron causing anaemia or making it worse ³. The gram negative gut bacteria H Pylori is also known to cause anemia, and the overgrowth of these bacteria is found in many individuals with migraines.

This means that even if you’re having an adequate iron intake from your diet or taking iron supplements, you may still become anemic due to chronic inflammation. The solution is to find and solve the root-cause of the inflammation then your iron levels should return to normal if your dietary intake is adequate.

¹ Tayyebi A, Poursadeghfard M, Nazeri M, Pousadeghfard T. Is There Any Correlation between Migraine Attacks and Iron Deficiency Anemia? A Case-Control Study. Int J Hematol Oncol Stem Cell Res. 2019 Jul 1;13(3):164-171. PMID: 31649807; PMCID: PMC6801325.

² Pagani A, Nai A, Silvestri L, Camaschella C. Hepcidin and Anemia: A Tight Relationship. Front Physiol. 2019;10:1294. Published 2019 Oct 9. doi:10.3389/fphys.2019.01294.

³ Nairz M, Theurl I, Wolf D, Weiss G. Iron deficiency or anemia of inflammation? : Differential diagnosis and mechanisms of anemia of inflammation. Wien Med Wochenschr. 2016 Oct;166(13-14):411-423. doi: 10.1007/s10354-016-0505-7. Epub 2016 Aug 24. PMID: 27557596; PMCID: PMC5065583.